NM_000244.3:c.435C>T is a synonymous variant (p.Ser145=) in exon 2 of the MEN1 gene. This variant is present at a high allele frequency in population databases: 2.84% overall in gnomAD v2.1 (8021/282758 alleles, 189 homozygotes) and 3.54% in gnomAD v4.1 (57090/1614046 alleles, 1240 homozygotes), with a maximum subpopulation frequency of 6.39% in the European (Finnish) population. This far exceeds the BA1 threshold of >1%, satisfying stand-alone benign evidence.1 The variant has been observed in a homozygous state in 189 individuals in gnomAD v2.1 and 1240 individuals in gnomAD v4.1. For a highly penetrant autosomal dominant disorder such as MEN1, the observation of multiple healthy adult homozygotes is incompatible with pathogenicity.2 SpliceAI predicts no splice impact (max delta score = 0.00), consistent with a silent synonymous change that does not alter normal splicing.3 ClinVar classifies this variant as Benign, with consensus across 18 clinical laboratories (ClinVar ID 96252).4 No pathogenic evidence was identified: no de novo occurrences, no functional studies demonstrating damage, no case-control enrichment, no cosegregation data, and no in silico predictions of pathogenicity. Under generic ACMG/AMP 2015 rules, BA1 (stand-alone benign) alone is sufficient for a Benign classification. The additional supporting benign criteria (BS2, BP2, BP4, BP6, BP7) further reinforce the benign interpretation.5
MEN1
Final classification
Benign
MEN1 c.435C>T · p.Ser145=
MEN1
NM_000244.3:c.435C>T is a synonymous variant (p.Ser145=) in exon 2 of the MEN1 gene.
gene-specific framework lacked a usable explicit final combination framework, so generic ACMG/AMP 2015 final-combination rules were applied as fallback; applied criteria: BA1 stand-alone benign, BS1 strong benign, BS2 supporting benign, BP2 supporting benign, BP4 supporting benign, BP6 supporting benign, BP7 supporting benign; combination = 1 stand-alone benign + 1 strong benign + 5 supporting benign, which maps to Benign.
Classification rationale
BA1BS1BS2BP2BP4BP6BP7
Benign
MEN1 c.435C>T
BA1 + BS1 + BS2 + BP2 + BP4 + BP6 + BP7
→
Benign
5
generic_acmg_combination_rules
Gene diagram
· NM_000244.3 · variants mapped to exon structure
MEN1
NM_000244.3
Fetching transcript structure from UCSC…
Applied criteria · 7 met · select any tile
Met
Not met
Not assessed
N/A
Strength
very strong
supporting
Pathogenic evidence
PVS
PS
PM
PP
Benign evidence
BA
BS
BP
—
—
—
Rationale
Select a criterion.
Sources
Evidence used
Gaps remaining
Rule
—
Research & evidence
Population frequency · supports benign
gnomAD v4.1
gnomAD v2.1
Population frequency
1240
homozygotes observed in gnomAD v4.1. Healthy biallelic carriers are difficult to reconcile with a fully penetrant loss-of-function disease allele.
Overall AF
57090 / 1,614,046
3.5%
Highest · European (Finnish)
6.4%
Homozygotes
1240
grpmax FAF
4.1%
Allele frequency by ancestry — gnomAD v4.1
observed in 9 of 9 groups
| Ancestry | Allele count | Frequency | Homozygotes |
|---|---|---|---|
| European (Finnish) | 4082 / 64,030 | 6.4% | 142 |
| European (non-Finnish) | 49109 / 1,179,924 | 4.2% | 1049 |
| Amish | 37 / 912 | 4.1% | 1 |
| Middle Eastern | 75 / 6,062 | 1.2% | 3 |
| Admixed American | 614 / 60,020 | 1% | 5 |
| South Asian | 694 / 91,084 | 0.76% | 2 |
| Ashkenazi Jewish | 207 / 29,604 | 0.7% | 2 |
| African/African American | 517 / 75,036 | 0.69% | 0 |
| East Asian | 4 / 44,876 | 0.0089% | 0 |
“
This variant is present in gnomAD v4.1 (AF= 0.0353707; MAF= 3.53707%, 57090/1614046 alleles, homozygotes = 1240) and has highest observed frequency in the European (Finnish) population (AF= 0.0637514; MAF= 6.37514%, 4082/64030 alleles, homozygotes = 142); grpmax FAF= 0.0413118.
189
homozygotes observed in gnomAD v2.1. Healthy biallelic carriers are difficult to reconcile with a fully penetrant loss-of-function disease allele.
Overall AF
8021 / 282,758
2.8%
Highest · European (Finnish)
6.4%
Homozygotes
189
grpmax FAF
4.2%
Allele frequency by ancestry — gnomAD v2.1
observed in 8 of 8 groups
| Ancestry | Allele count | Frequency | Homozygotes |
|---|---|---|---|
| European (Finnish) | 1606 / 25,120 | 6.4% | 63 |
| European (non-Finnish) | 5315 / 129,094 | 4.1% | 110 |
| Remaining individuals | 233 / 7,218 | 3.2% | 7 |
| Admixed American | 376 / 35,424 | 1.1% | 6 |
| Ashkenazi Jewish | 81 / 10,368 | 0.78% | 2 |
| South Asian | 234 / 30,614 | 0.76% | 1 |
| African/African American | 173 / 24,968 | 0.69% | 0 |
| East Asian | 3 / 19,952 | 0.015% | 0 |
“
This variant is present in gnomAD v2.1 (AF= 0.028367; MAF= 2.83670%, 8021/282758 alleles, homozygotes = 189) and has highest observed frequency in the European (Finnish) population (AF= 0.0639331; MAF= 6.39331%, 1606/25120 alleles, homozygotes = 63); grpmax FAF= 0.0423484.
“
This variant is absent from gnomAD-Canada.
ClinVar
This variant has been reported in ClinVar as Benign (18 clinical laboratories). (ClinVarID = 96252)
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00).
Functional
Unknown Oncogenic Effect
OncoKB identified curated literature and non-variant-specific oncogenicity context for review; listed oncogenicity label: Unknown Oncogenic Effect.
COSMIC
Cancer hotspots
Somatic evidence
Not in COSMIC / hotspots
COSMIC
This variant does not lie in a statistically significant hotspot. This variant has previously been reported in somatic cancers (COSMIC; COSV56341605, n = 2 times).
Hotspots
This variant does not lie in a statistically significant hotspot.
Literature · 19 PMIDs triaged · 8 high-priority
19papers screened
Papers triaged by theme: functional/splicing/segregation/case_observation. high_priority_papers include abstract snippets. Use these to support PS3/BS3/PS4/PP1/PP3/PP5.
10090472 ↗
splicing rna
Germline mutations in the multiple endocrine neoplasia type 1 gene: evidence for frequent splicing defects.
Multiple endocrine neoplasia type 1 (MEN 1) is a familial cancer syndrome characterized by parathyroid hyperplasia, pituitary adenomas, and neuroendocrine tumors of the pancreas and duodenum. In 1997, the MEN1 tumor suppressor gene was identified, and numerous germline mutations have been reported to be distributed throughout the gene. We used single strand conformational variant (SSCV) analysis t
BP7PP3PS3PS4PVS1
10634422 ↗
splicing rna
Complete sequencing and messenger ribonucleic acid expression analysis of the MEN I gene in adrenal cancer.
Adrenal cancer is a rare sporadic disease that has also been observed in the context of multiple endocrine neoplasia type I (MEN I). Adrenal lesions occur in up to 40% of MEN I patients. Loss of heterozygosity of the 11q13 band harboring the menin gene has been reported in more than 50% of patients with adrenal cancer. Despite this high index of suspicion, former screening studies did not reveal m
BP7PP3PS3PS4PVS1
10843194 ↗
segregation
Familial hypercalcemia and hypercalciuria caused by a novel mutation in the cytoplasmic tail of the calcium receptor.
Familial hyperparathyroidism (HPT), characterized by hypercalcemia and hypercalciuria, and familial benign hypocalciuric hypercalcemia (FHH) are the most common causes of hereditary hypercalcemia. The calcium-sensing receptor (CaR) regulates PTH secretion and renal calcium excretion. Heterozygous inactivating mutations of the gene cause FHH, whereas CaR gene mutations have not been demonstrated in
BS4PP1PS3PS4
11807402 ↗
segregation
Familial isolated hyperparathyroidism: clinical and genetic characteristics of 36 kindreds.
BS4PP1PS3PS4
17623761 ↗
functional
Clinical testing for mutations in the MEN1 gene in Sweden: a report on 200 unrelated cases.
Multiple endocrine neoplasia type 1 (MEN1) is a tumor syndrome of the parathyroid, endocrine pancreas, and anterior pituitary caused by mutations in the MEN1 gene on 11q13. The goal of this study was to determine the MEN1 mutation spectrum and detection rate among Swedish patients and identify which patient categories should be tested for MEN1 mutations. DNA sequences and referral forms from patie
BS3PS3PS4
17953629 ↗
splicing rna
MEN1 gene mutations in Hungarian patients with multiple endocrine neoplasia type 1.
Multiple endocrine neoplasia type 1 (MEN1) is an autosomal dominant hereditary disorder associated with mutations of the MEN1 gene. MEN1 may present as a familial or a sporadic disorder, with multiple endocrine tumours including parathyroid adenomas or hyperplasias, and pancreatic endocrine and pituitary gland tumours. The aim of this study was to examine the prevalence and spectrum of MEN1 gene m
BP7PP3PS3PS4PVS1
25741868 ↗
functional
Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology.
The American College of Medical Genetics and Genomics (ACMG) previously developed guidance for the interpretation of sequence variants.(1) In the past decade, sequencing technology has evolved rapidly with the advent of high-throughput next-generation sequencing. By adopting and leveraging next-generation sequencing, clinical laboratories are now performing an ever-increasing catalogue of genetic
BS3PS3PS4
26467025 ↗
functional
A Standardized DNA Variant Scoring System for Pathogenicity Assessments in Mendelian Disorders.
We developed a rules-based scoring system to classify DNA variants into five categories including pathogenic, likely pathogenic, variant of uncertain significance (VUS), likely benign, and benign. Over 16,500 pathogenicity assessments on 11,894 variants from 338 genes were analyzed for pathogenicity based on prediction tools, population frequency, co-occurrence, segregation, and functional studies
BS3PS3PS4
28492532 ↗
background review
Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria.
PS3PS4
Sources & reference links